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Home , Extrapyramidal symptoms, Status epilepticus

Treatment in Psychiatry

Treatment in Psychiatry begins with a hypothetical case illustrating a problem in current clinical practice. The authors review current data on prevalence, diagnosis, pathophysiology, and treatment. The article concludes with the authors' treatment recommendations for cases like the one presented. Neuroleptic Malignant Syndrome

Jeffrey R. Strawn, M.D. Does this patient have neuroleptic malig- nant syndrome (NMS)? What are the risk Paul E. Keck, Jr., M.D. factors for NMS? What are the most sen- sitive diagnostic criteria? What is known Stanley N. Caroff, M.D. about the pathophysiology of this condi- tion? What treatment strategies are available and what treatments should be initiated?

“Ms. A,” a 25-year-old woman with para- noid , presented with an Scope and Nature of Neuroleptic acute psychotic episode after having Malignant Syndrome stopped taking her . She re- ported auditory hallucinations and was NMS, first described nearly five decades ago, is an idio- noted to be disheveled and to have loud, syncratic, life-threatening complication of treatment with pressured speech, disorganization of drugs that is characterized by fever, severe thought processes, and persecutory delu- muscle rigidity, and autonomic and mental status changes sions. Over a 10-hour period in the emer- (1, 2). Although estimates of the incidence of NMS once gency department, she received two in- ran as high as 3% of patients treated with , tramuscular injections of (5 more recent data suggest an incidence of 0.01%–0.02% (3). mg each) and required intermittent phys- This decrease in frequency likely reflects increased aware- ical restraint for safety. Her prior regimen ness of the disorder, more conservative prescribing pat- of 10 mg/day of oral haloperidol and 1 terns, and the shift to use of atypical antipsychotics. In mg/day of benztropine was resumed. addition, progression to more fulminant, lethal NMS epi- sodes may occur less often because of widespread recog- The following morning, Ms. A was noted nition and earlier diagnosis of this drug-induced reaction. to be diaphoretic and in moderate dis- Despite its declining frequency, however, NMS remains a tress. Her heart rate was 140 bpm, blood significant source of morbidity and mortality among pa- pressure 145/92 mmHg, respiratory rate tients receiving antipsychotics. For example, data from the 26 breaths per minute, and temperature U.S. Agency for Healthcare Research and Quality indicate 104.5°F (rectal). Physical examination that about 2,000 cases of NMS are diagnosed annually in demonstrated generalized rigidity and hospitals in the , incurring health care costs tremulousness in all extremities, and her mental status was consistent with delir- of $70 million, with a mortality rate of 10%, which under- ium. Laboratory studies were remarkable scores the continuing public health impact of NMS (http:/ for a white blood cell count of 15,000 /hcup.ahrq.gov/HCUPnet.asp). cells/ml and a creatine kinase level of 45,050 IU. Levels of serum transaminases Diagnosis were elevated, but levels of electrolytes, Despite the availability of operational criteria (4, 5), blood urea nitrogen, and creatinine were NMS is often difficult to distinguish from more common all within normal limits, and a urine toxi- extrapyramidal side effects of antipsychotics and from cology screen was negative. Results of a other disorders presenting with similar symptoms (6–8). CSF examination were normal, and cul- DSM-IV-TR research criteria require that both severe mus- tures of blood and urine were negative. A cle rigidity and elevated temperature be present after re- chest X-ray was normal. Electroencepha- cent administration of an antipsychotic as well as two as- lography demonstrated diffuse, general- sociated signs, symptoms, or laboratory findings that are ized slowing, and computed tomography not better accounted for by a substance-induced, neuro- revealed no acute intracranial pathology. logical, or general medical condition. Rating scales have

This article is featured in this month’s AJP Audio and is the subject of a CME course.

870 ajp.psychiatryonline.org Am J Psychiatry 164:6, June 2007 TREATMENT IN PSYCHIATRY been introduced for tracking the clinical course of NMS on cases reported to the Neuroleptic Malignant Syndrome In- the basis of factors such as severity of , rigid- formation Service, infections, agitated , and be- ity, mental status alteration, and elevation in serum crea- nign extrapyramidal symptoms are among the processes tine kinase (9, 10). most commonly confused with NMS (S.N. Caroff, unpub- Laboratory investigations are essential to exclude other lished data, 2007). disorders or complications. Several laboratory abnormali- In the , special attention should be ties are associated with NMS, although none are specific given to the evaluation of CNS infections, especially viral for the diagnosis (7, 8). For example, patients with NMS , which can be difficult to distinguish from may have , resulting in significant in- NMS. Prodromal viral illnesses, , meningeal creases in serum creatine kinase, aldolase, transaminases, signs, , localizing neurological signs, CSF studies, and lactic acid dehydrogenase con- and neuroimaging may suggest an infec- centrations, with the risk of subse- tious etiology. Caroff and Mann (7) noted quent myoglobinuric renal failure. Pa- “Differential diagnosis that the risk of severe drug-induced ex- tients may also have metabolic trapyramidal reactions, including NMS, acidosis, hypoxia, decreased serum is of prime importance may be heightened in patients infected iron concentrations, elevated serum because NMS is a by HIV and other viruses that affect mid- catecholamines, and leukocytosis, brain structures. Anatomic lesions affect- with or without left shift. Results of diagnosis of exclusion.” ing midbrain and brainstem structures, CSF analysis are normal in more than as well as rare cases of nonconvulsive sta- 95% of cases (11). Findings of neu- tus epilepticus, can simulate NMS and roimaging studies are generally within normal limits, and are considered in the differential diagnosis. may demonstrate generalized Advanced stages of psychotic disorders associated with slowing consistent with metabolic (11). excited or stuporous (delirious mania and ma- The temporal progression of may lignant catatonia) can present with hyperthermia and ap- provide important clues to diagnosis and severity of ill- pear indistinguishable from NMS (14). Indeed, NMS has ness. Retrospective analyses suggest that alteration in been conceptualized as a drug-induced iatrogenic form of mental status and other neurological signs precede sys- malignant catatonia (14, 15). Although some features— temic signs in more than 80% of cases of NMS (8, 12). Al- such as parkinsonian symptoms; extreme hyperthermia though the initial progression of symptoms is usually in- and developing only after drug administration; ab- sidious over days, occasional cases of NMS may have a sence of an underlying psychiatric disorder; and so on— fulminant onset within hours after drug administration. may be suggestive of drug-induced malignant catatonia About 16% of cases of NMS develop within 24 hours after (i.e., NMS) rather than idiopathic malignant catatonia due initiation of antipsychotic treatment, 66% within the first to progression of psychotic illness, the two conditions may week, and virtually all cases within 30 days (11). It would be indistinguishable in more than 20% of cases and may be unusual for NMS to occur beyond 1 month after initia- reflect the same underlying pathophysiology (14). In ei- tion of treatment unless the dose was increased or an ad- ther NMS or malignant catatonia due to , anti- ditional antipsychotic administered. Once NMS is diag- psychotics should be discontinued; most NMS episodes nosed and oral antipsychotic drugs are discontinued, are self-limited once medication is stopped, and in idio- NMS is self-limited in most cases. The mean recovery time pathic malignant catatonia, antipsychotics appear to be after drug discontinuation is in the range of 7–10 days, ineffective or even detrimental. ECT appears to be the with 63% of patients recovering within 1 week and nearly treatment of choice in malignant catatonia, and it is often all within 30 days (11). However, the duration of NMS epi- effective in NMS as well. sodes may be prolonged when long-acting depot antipsy- Among systemic disorders, heatstroke can present with chotics are implicated. In addition, there have been sev- hyperthermia, confusion, tachycardia, and tachypnea, eral reports of patients in whom residual catatonia and and its differentiation from NMS may be difficult in a psy- persisted for weeks after the acute meta- chiatric patient receiving antipsychotic medication. How- bolic symptoms of NMS resolved (8, 13). Clinicians should ever, in heatstroke patients, in addition to a history of ex- bear in mind that although NMS is striking in its classic ertion or exposure to high ambient temperatures, the skin form, the condition is heterogeneous in onset, presenta- is dry and muscle flaccidity is commonly observed. tion, progression, and outcome. Several classes of drugs may cause symptoms resem- bling those of NMS. Dopamine antagonists other than an- Differential Diagnosis tipsychotic drugs (e.g., , , and ) have reportedly caused NMS. With- Differential diagnosis (Table 1) is of prime importance drawal of dopaminergic agents (e.g., and L- because NMS is a diagnosis of exclusion. Central, sys- dopa) or of the GABA-ergic drug baclofen can precipitate temic, and toxic causes of hyperthermia and rigidity must an NMS-like reaction. Serotonergic drugs, including selec- be excluded, as well as other causes of rhabdomyolysis tive serotonin reuptake inhibitors, tricyclic antidepres- and altered mental status. According to a compilation of sants, monoamine oxidase inhibitors (including line-

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TABLE 1. Differential Diagnosis of Neuroleptic Malignant CNS dopamine activity or receptor function, and iron de- Syndrome ficiency (18, 19). Nearly all case series of NMS patients Infectious have reported physical exhaustion and dehydration prior or encephalitis Postinfectious syndrome to the onset of NMS (17). Elevated environmental temper- ature has been proposed as a contributing factor in some Sepsis series, although NMS can occur independent of ambient Psychiatric or neurological conditions. A prior episode of NMS has been described in Idiopathic malignant catatonia Agitated delirium 15%–20% of cases (8, 11). Benign extrapyramidal side effects Pharmacological and treatment variables have been ex- Nonconvulsive status epilepticus amined as risk factors for NMS. Nearly all dopamine an- Structural lesions, particularly involving the midbrain Toxic or pharmacological tagonists have been associated with NMS, although high- delirium potency conventional antipsychotics are associated with a Salicylate poisoning greater risk compared with low-potency agents and atypi- Malignant hyperthermia (inhalational anesthetics, cal antipsychotics (3, 7). Parenteral routes, higher titration succinylcholine) (monoamine oxidase inhibitors, triptans, rates, and total dose of drug administration have been as- linezolid) sociated with an increased risk of NMS (17); however, a Substances of abuse (amphetamines, hallucinogens) significant number of NMS cases occur at therapeutic Withdrawal from dopamine agonists, baclofen, sedative- hypnotics, and alcohol doses of these agents. Although cases of NMS meeting Endocrine DSM-IV-TR research criteria have been reported with Thyrotoxicosis , , and , unequivocal cases Pheochromocytoma implicating monotherapy with , , or Environmental Heatstroke remain scarce (20). Although evidence from small cohort studies suggests that these clinical and pharmacological variables correlate zolid), and triptans used to treat headaches, can with the risk of NMS, they are not practical in predicting cause serotonin syndrome, which most often presents as risk in a given patient because they are relatively common an agitated delirium but resembles NMS in severe cases. It and NMS is relatively uncommon. In other words, the as- is important to differentiate between serotonin syndrome sociation of these risk factors with NMS in a few patients and NMS not only because the treatment approaches for may not outweigh the benefits of antipsychotics for the the two conditions may differ but also because the diag- vast majority of psychotic patients. nosis will affect how one approaches resumption of anti- psychotic medication in patients with persistent or recur- Pathophysiology rent psychosis. Patients undergoing general anesthesia may develop Although the precise pathophysiological mechanisms the NMS-like signs of malignant hyperthermia. In contrast of NMS are unproven, antipsychotic-induced dopamine to NMS, these patients usually develop symptoms intra- blockade likely plays a pivotal triggering role in the condi- operatively, have a primary pharmacogenetic skeletal tion (Figure 1) (21). This hypothesis is supported by sev- muscle disorder (which consequently is not relieved by eral lines of evidence: withdrawal of dopaminergic drugs neuromuscular blocking agents), and may have a family can precipitate an NMS-like syndrome; all drugs associ- history of malignant hyperthermia during surgery (8, 16). ated with NMS produce dopamine receptor blockade; the Certain substances of abuse are associated with NMS- risk of NMS appears to be correlated with the dopamine- like presentations, among them cocaine and amphet- receptor-binding affinity of drugs; dopaminergic drugs amine (especially Ecstasy [3,4-methylenedioxymetham- have been used in treatment of NMS symptoms; and pa- phetamine, or MDMA]). Hallucinogen intoxication (e.g., tients with central dopamine tract lesions have been from phencyclidine) and withdrawal from alcohol and sed- noted to develop syndromes that share many clinical ative-hypnotics also may cause fever, autonomic changes, characteristics with NMS. The central role of dopaminer- and other symptoms that can be confused with NMS. gic hypofunction is further supported by the observation that the CSF concentration of the dopamine metabolite Risk Factors homovanillic acid is low in patients with acute NMS (22). A number of preliminary studies have searched for poly- Several studies of risk factors for NMS (17) suggest that morphisms within the dopamine 2 receptor gene in pa- age, sex, and time of year are not significantly correlated tients who have recovered from NMS, although results with risk of developing the condition. NMS is not specific have not been consistent (8). to any neuropsychiatric diagnosis, although patients with Based on the autonomic dysfunction described over the catatonia may be at risk of progressing to NMS after re- past two decades in NMS and the observation that cate- ceiving antipsychotics. cholamine levels are elevated in many cases, sympathoadre- Several clinical, systemic, and metabolic factors have nal dysfunction has been suggested as having a contributing been correlated with the incidence of NMS, including agi- role in NMS (23, 24). Whatever the initiating mechanism, tation, dehydration, restraint, preexisting abnormalities of the pathophysiology of NMS is likely complex, involving a

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FIGURE 1. Simplified Pathophysiology of Neuroleptic Malignant Syndrome (NMS), Including Elements of Sympathoadrenal Dysregulationa

Increased muscle Myonecrosis, rhabdomyolysis, and increased creatine kinase Hyperthermia Muscle rigidity

Myoglobinuria Hypothalamic Nigrostriatal Extrapyramidal dopamine blockade blockade symptoms

Frontal lobe Granulocytosis, Altered dysfunction Dopamine Sympathetic incontinence, mental and/or antagonist diaphoresis, tachycardia, status mesocortical labile blood pressure blockade ? Labile hypertension, Vasomotor Dehydration tachycardia Autonomic dysfunc- tion (loss of hierarchi- cal integration and control) Adreno- Tachycardia, medullary tachypnea, diaphoresis a Adapted from Gurrera (24). cascade of dysregulation in multiple neurochemical and tate recovery and improve outcome. It is difficult to com- neuroendocrine systems culminating in an end-stage hy- pare specific treatments for NMS because the disorder is permetabolic syndrome. rare, heterogeneous, and unpredictable in onset and pro- gression, which precludes randomized controlled studies. Treatment and Management However, theoretical grounds and numerous clinical re- ports provide some support for several empirical, off-label Supportive Therapy treatment approaches (26). The offending agent must be withdrawn immediately, . Although a controlled evaluation of after which supportive medical therapy is the mainstay of NMS risk factors suggests that benzodiazepines do not management of NMS (25, 26). Table 2 presents a treatment have a preventive effect (17), several clinical reports sug- algorithm for NMS, including clinical presentation by ill- gest that benzodiazepines, administered orally or ness stage or severity. Volume resuscitation should be ag- parenterally, may ameliorate symptoms and hasten recov- gressive, especially given that most patients with NMS are ery in NMS, particularly in milder cases. This observation dehydrated in the acute phase of the illness. Serial moni- is not surprising given that NMS has been considered an toring and correction of electrolyte abnormalities is criti- extreme form of catatonia (25, 28). However, there have cal. Recent reports suggest that alkalinized fluids or even been reports of cases of acute NMS in which benzodiaz- bicarbonate loading may be of particular benefit in pre- epines had no clinical effect or produced only transient venting renal failure (27). In extreme hyperthermia, physi- clinical improvement. Nonetheless, given the relative risks cal cooling measures are paramount, as the peak and du- and benefits, a trial of , starting with 1–2 mg ration of temperature elevation are predictive of morbidity parenterally, is a reasonable first-line intervention in pa- and mortality (8). Intensive medical care should include tients with acute NMS, particularly in those with milder careful monitoring for complications, including cardio- and primarily catatonic symptoms. respiratory failure, renal failure, aspiration pneumonia, and coagulopathies, and may involve support of cardiac, Dopaminergic Agents. Several dopaminergic drugs, in- respiratory, and renal function. cluding bromocriptine and amantadine, may reverse par- kinsonism in NMS and have been reported in case reports Pharmacological Treatments and meta-analyses (8, 29, 30) to reduce time to recovery NMS is a self-limited iatrogenic disorder, and in many and halve mortality rates when used alone or in combina- cases medical management and cessation of antipsy- tion with other treatments. Amantadine is generally initi- chotic medication may suffice to reverse the symptoms. ated at 200–400 mg/day in divided doses administered There is no general consensus on specific pharmacologi- orally or through a nasogastric tube. The starting dose of cal treatments for uncomplicated NMS, and there is only bromocriptine is 2.5 mg orally two or three times a day, in- limited evidence on whether specific remedies can facili- creased to a total daily dose of 45 mg if necessary. Bro-

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TABLE 2. Proposed Treatment Algorithm for Neuroleptic Malignant Syndrome (NMS) Spectrum-Related Symptoms Woodbury Stagea Clinical Presentation Supportive Care First-Line Interventions Second-Line Interventions Stage I: drug-induced Rigidity; tremor Reduce or switch antipsy- Anticholinergic agents parkinsonism chotics Stage II: drug-induced Rigidity; mutism; stupor Discontinue, reduce, or Lorazepam (1–2 mg i.m. or catatonia switch antipsychotics i.v. every 4–6 hr) Stage III: mild, early Mild rigidity; catatonia or Discontinue antipsychotics, Lorazepam (1–2 mg i.m. or NMS confusion; temperature carefully monitor for i.v. every 4–6 hr) ≤38°C (100.4°F); heart progression, correct risk rate ≤100 bpm factors Stage IV: moderate NMS Moderate rigidity; catatonia Discontinue antipsychotics, Lorazepam (1–2 mg i.m. or Consider electroconvulsive or confusion; tempera- manage fluids, initiate i.v. every 4–6 hr), bro- therapy (6–10 bilateral ture 38–40°C (100.4– cooling measures, correct mocriptine (2.5–5 mg p.o. treatments) 104°F); heart rate 100– risk factors, provide inten- or by nasogastric [NG] 120 bpm sive care tube every 8 hr), or aman- tadine (100 mg p.o. or by NG tube every 8 hr) Stage V: severe NMS Severe rigidity; catatonia or Discontinue antipsychotics, Dantrolene (1–2.5 mg/kg Consider electroconvulsive ; temperature ≥40°C manage fluids, initiate body weight i.v. every 6 hr therapy (6–10 bilateral (104°F); heart rate ≥120 cooling measures, correct for 48 hr, tapered), bro- treatments) bpm risk factors, provide inten- mocriptine (2.5–5 mg p.o. sive care or by NG tube every 8 hr), or amantadine (100 mg p.o. or by NG tube every 8 hr) a Adapted from Woodbury and Woodbury (25). mocriptine can worsen psychosis and hypotension. It also occur after the first few days of treatment. In contrast, ECT may precipitate vomiting and thus should be used care- may be effective if symptoms are refractory to supportive fully in patients at risk of aspiration. Premature discontin- care and pharmacotherapy even late in the course of NMS, uation of bromocriptine has resulted in rebound symp- or if idiopathic malignant catatonia due to an underlying toms in some cases. psychotic disorder cannot be excluded, or if the patient Dantrolene. Because of its efficacy in anesthetic-in- has persistent residual catatonia and parkinsonism after duced malignant hyperthermia, the muscle relaxant dan- resolution of the acute metabolic symptoms of NMS. trolene has been used in the treatment of NMS. Dan- A review (32) found that ECT was consistently effective trolene may be useful only in cases of NMS with extreme even after failed pharmacotherapy and that clinical re- temperature elevations, rigidity, and true hypermetabo- sponse often occurred over the course of the first several lism (8). Generally, rapid reversal of the hyperthermia and treatments. Treatment response to ECT was not pre- rigidity is observed in patients treated with dantrolene, dicted by age, sex, psychiatric diagnosis, or any particu- but symptoms may return if treatment is discontinued lar features of NMS. A typical ECT regimen for acute NMS prematurely. Dantrolene can be combined with benzodi- would include six to 10 treatments with bilateral elec- azepines or dopamine agonists, but it should not be coad- trode placement. ECT is a relatively safe treatment in ministered with calcium channel blockers, as cardiovas- NMS, although use of succinylcholine during anesthesia cular collapse can occur. Typical dosing of intravenous should be carefully considered in patients with severe dantrolene in the treatment of NMS is 1–2.5 mg/kg body rhabdomyolysis to avoid the risk of hyperkalemia and weight administered initially, followed by 1 mg/kg every 6 cardiovascular complications. hours if rapid resolution of the fever and rigidity is ob- served, with tapering or switching to oral dantrolene after Antipsychotic Use Following NMS the first few days. Side effects may include impairment of respiratory or hepatic function. In some meta-analyses (8, Restarting antipsychotic treatment after resolution of an 29, 30), improvement has been reported in approximately NMS episode has been associated with an estimated likeli- 80% of NMS patients treated with dantrolene monother- hood of developing NMS again as high as 30% (11, 33). apy. In addition, time to recovery may be shortened, and Nevertheless, most patients who require antipsychotic mortality is decreased by nearly half compared with sup- treatment can be safely treated, provided precautions are portive care, whether dantrolene is used alone or in com- taken (7). For example, reports of previous episodes should bination with other agents. However, other anecdotal re- be checked for accuracy; indications for antipsychotics ports and a recent meta-analysis of published cases did should be clearly documented; alternative not support the efficacy of dantrolene in NMS (31). should be considered; risk factors should be reduced; at least 2 weeks should be allowed to elapse after recovery ECT from NMS before rechallenge; low doses of low-potency As the above suggests, pharmacotherapy has not been conventional antipsychotics or atypical antipsychotics consistently effective in all case reports of NMS. Moreover, should be titrated gradually after a test dose; and patients drug effects are usually observed early and are unlikely to should be carefully monitored for early signs of NMS. In

874 ajp.psychiatryonline.org Am J Psychiatry 164:6, June 2007 TREATMENT IN PSYCHIATRY addition, prudence dictates that documented informed of Cincinnati, Department of Psychiatry, Box 670559, Cincinnati, OH consent should be obtained from patients and family 45267-0559; [email protected] (e-mail). members regarding the benefits of restarting antipsychotic CME Disclosure therapy versus the risk of recurrence of NMS. There are no Dr. Strawn reports no competing interests. Dr. Keck has received re- data on rechallenging patients who recover from idio- search support from or served in an advisory or consulting capacity pathic malignant catatonia with antipsychotics, but fol- for Abbott Laboratories, American Diabetes Association, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly and lowing the same precautions as for NMS would be sensible. Company, Janssen Pharmaceutica, National Institute of Mental Health, National Institute of Drug Abuse, Pfizer, Stanley Medical Re- search Institute, and UCB Pharma. He is a patent holder for a Summary and Recommendations method of treating obsessive-compulsive spectrum disorder (Patent No. 6,387,956). Dr. Caroff has received research support from Bristol- The incidence of NMS is estimated at 0.01%–0.02% of Myers Squibb, Ortho-McNeil Neurologics, and Pfizer. patients treated. Although the widespread adoption of APA policy requires disclosure by CME authors of unapproved or in- atypical antipsychotics has markedly reduced the risk of vestigational use of products discussed in CME programs. Off-label use of medications by individual physicians is permitted and com- neurological disorders, NMS remains a risk for susceptible mon. Decisions about off-label use can be guided by scientific litera- patients receiving these drugs. The atypical agents are as- ture and clinical experience. sociated with less risk of NMS than the conventional an- tipsychotics. Nevertheless, clinicians must be aware of the References clinical features of NMS and vigilant in detecting early signs. Primary management of NMS lies in prevention 1. Delay J, Pichot P, Lempérière T, Elissade B, Peigne F: Un neuro- leptique majeur non-phénothiazine et nonréserpinique, l’ha- through conservative use of antipsychotics, reduction of lopéridol, dans le traitement des psychoses. Annales Médico- risk factors, early diagnosis, prompt discontinuation of of- Psychologique 1960; 118:145–152 fending medications, and medical management. In the 2. Caroff SN: The neuroleptic malignant syndrome. J Clin Psychia- absence of randomized controlled trials, it may be unwar- try 1980; 41:79–83 3. Stubner S, Rustenbeck E, Grohmann R, Wagner G, Engel R, ranted to recommend one single intervention over an- Neundorfer G, Moller HJ, Hippius H, Ruther E: Severe and un- other or over supportive management. Specific treatment common involuntary movement disorders due to psychotro- of NMS should be individualized and based empirically on pic drugs. Pharmacopsychiatry 2004; 37(suppl 1):S54–S64 the character, duration, and severity or stage of clinical 4. Pope HG Jr, Keck PE Jr, McElroy SL: Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hos- signs and symptoms (25, 26). For mild cases, supportive pital. Am J Psychiatry 1986; 143:1227–1233 care and careful clinical monitoring may be sufficient (7, 5. American Psychiatric Association: Diagnostic and Statistical 8), whereas in severe cases, more aggressive measures Manual of Mental Disorders, 4th ed. 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J Clin Psy- be initiated at a low dose and slowly titrated in a moni- chopharmacol 2000; 20:257–259 tored setting with careful assessment for signs of recur- 14. Mann SC, Caroff SN, Bleier HR, Welz WK, Kling MA, Hayashida M: Lethal catatonia. Am J Psychiatry 1986; 143:1374–1381 rent NMS. 15. Fink M: Neuroleptic malignant syndrome and catatonia: one entity or two? Biol Psychiatry 1996; 39:1–4 Received Feb. 5, 2007; revision received Feb. 11, 2007; accepted 16. Caroff SN, Rosenberg H, Mann SC, Campbell EC, Gliatto MF, Sul- Feb. 22, 2007. From the Department of Psychiatry, College of Medi- livan KA: Neuroleptic malignant syndrome in the perioperative cine, University of Cincinnati, Cincinnati; the Department of Psychia- setting. Am J Anesthesiol 2001; 28:387–393 try, University of Pennsylvania School of Medicine, Philadelphia; and 17. Keck PE Jr, Pope HG Jr, Cohen BM, McElroy SL, Nierenberg AA: the Department of Veterans Affairs Medical Center, Philadelphia. 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